The overall goal of this project is to develop mucosally targeted subunit vaccines that can elicit potent mucosal and systemic neutralizing antibodies and major histocompatibility compels (MHC) class I restricted cytotoxic T-lymphocyte (CTL) responses to human immunodeficiency virus type 1 (HIV-1) and HIV-1 infected cells. Specific aims are as follows: Specific Aim 1. We will test the chimeric HIV peptide T1-SP10MN(A) administered to the mucosal surface of rabbits via chronically isolated ileal loops (Thiry-Vella model) for induction of HIV-neutralizing secretary IgA (S-IgA) and IgG in vaginal and gastrointestinal secretions and in serum. Specific Aim 2. We will incorporate mucosal adjuvants and the HIV peptide T1-SP10MN (A) into biodegradable poly (DL-lactide-co-glycoside) (DL-PLG) microsphere, administer these parenterally and orally to Balb/mice, and evaluate mucosal anti-HIV-1 S-IgA, IgG and MHC class I- restricted CTL responses. Specific Aim 3. We will characterized the mucosal immune response to parental immunization with the T1-Sp10MN (A) peptide in normal subjects. Specific Aim 4. We will assess in rhesus monkeys a peptide/adjuvant/microsphere inoculum designed to optimize an anti-HIV envelope mucosal immune response. Specific Aim 5. To study the ability of IgA to neutralize HIV-1, we will produce IgA monoclonal antibodies to the V3 domain of HIV-1 MN gp120 and measure their ability to neutralize HIV-1 and enhance HIV-1 infection in the presence and absence of complement.